Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

Article abstract of DOI:10.3762/bjoc.12.118

Starting fromγ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally define

Full text of DOI:10.3762/bjoc.12.118

Stereoselective synthesis of tricyclic compounds by
intramolecular palladium-catalyzed addition of
aryl iodides to carbonyl groups
Jakub Saadi, Christoph Bentz, Kai Redies, Dieter Lentz, Reinhold Zimmer
and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1236–1242.
Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustrasse 3, D-14195 Berlin, Germany
doi:10.3762/bjoc.12.118
Received: 29 March 2016
Accepted: 01 June 2016
Published: 16 June 2016
Email:
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
* Corresponding author
This article is part of the Thematic Series "Organometallic chemistry" and
is dedicated to the memory of Professor Peter Hofmann.
Keywords:
1,2-addition; aryl iodides; ketones; nucleophilic addition; palladium
catalysis
Guest Editor: B. F. Straub
© 2016 Saadi et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Starting from γ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively
led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally defined the
structure of crucial cyclization products. The relative configuration of the precursor compounds is essentially transferred to that of
the products and the formed hydroxy group in the newly generated cyclohexane ring is consistently in trans-arrangement with
respect to the methoxycarbonyl group. A transition-state model is proposed to explain the observed stereochemical outcome. This
palladium-catalyzed Barbier-type reaction requires a reduction of palladium(II) back to palladium(0) which is apparently achieved
by the present triethylamine.
Introduction
For our systematic studies on samarium diiodide promoted [A: R1–R2 = (CH2)4] typical Heck reaction conditions employ-
cyclizations leading to benzannulated medium-sized rings [1-4] ing styrene as olefin component not only led to the desired
we required starting materials such as alkenyl-substituted com- styrene derivative B but mainly to the cyclized product C. If the
pounds B (Scheme 1). Obvious precursors for B are aryl iodides reaction was performed without the olefin it provided only the
A that smoothly undergo palladium-catalyzed coupling reac- tertiary alcohol C in reasonable yield [5]. Similar C–C bond
tions to provide the desired products. However, in one case forming reactions of aryl halides that involve an insertion of the
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Beilstein J. Org. Chem. 2016, 12, 1236–1242.
Scheme 1: Planned Heck reaction of A to compound B and serendipi-
tous discovery of the palladium-catalyzed cyclization to products C.
Scheme 2: Synthesis of compounds A (1–6) via methyl 2-siloxycyclo-
propanecarboxylates D, their alkylation to E and fluoride-induced ring
opening.
intermediate aryl palladium species into a carbonyl group are
relatively rare (see discussion below). Therefore this serendipi-
tous discovery led us to investigate the reaction in more detail.
NEt3, DMF, 110 °C, 3 d) that had been optimized with com-
pound 4 a moderate yield of the tetralin derivative 7 formed as a
single diastereomer (Scheme 3). Although the configurational
Results
The required γ-ketoesters A bearing the aryl iodide substituent assignment is ambiguous in this case, the NMR data and the
were prepared following our well-established route via 2-sil- fact that no γ-lactone is formed strongly support the trans-
oxycyclopropane carboxylates D [6,7] that allows a regioselec- arrangement of the two functional groups as depicted. Under
tive introduction of the benzylic substituents at the α-carbon similar conditions (5 mol % Pd(PPh3)4, 90 °C, 3 d) the iso-
[8,9] to give intermediates E (Scheme 2). After fluoride-pro- propyl-substituted ketone 2 furnished a mixture of the related
moted ring opening [10] the desired precursor compounds A trans-compound 8 (11%) together with the de-iodinated prod-
(1–6) were obtained in reasonable overall efficacies (for details uct 9 (25%) and the indane derivative 10 as major component
see Supporting Information File 1).
(62%). The C–C coupling reaction to 8 seems to be hindered in
this case, probably due to the steric bulk of the isopropyl group.
We start our report with the palladium-catalyzed reactions of The formation of indane derivative 10 occurs by an intramole-
simple alkyl ketones 1 and 2 leading to bicyclic products and cular enolate arylation, a reaction that has been discovered by
then continue with the transformations of cyclic ketones 3–6 our group some years ago [11,12]. Apparently, under the reac-
that led to tricyclic compounds. Methyl ketone 1 provided under tion conditions a ketone enolate of 2 reacts with the iodoarene
the reaction conditions (2 mol % Pd(PPh3)4, 3.5 equivalents moiety to form the five-membered ring of 10. The configura-
Scheme 3: Palladium-catalyzed reactions of methyl ketone 1 to tetralin derivative 7 and of isopropyl-substituted ketone 2 to compounds 8, 9 and 10.
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Beilstein J. Org. Chem. 2016, 12, 1236–1242.
tional assignments of compounds 7 and 8 are in agreement with
those discussed below, where X-ray crystal structure analyses
unequivocally confirmed the relative configurations of cycliza-
tion products.
With the cyclic ketones in part considerably higher yields of
tricyclic products could be obtained (Schemes 4–6). The
cyclopentanone derivative 3 (Scheme 4) had to be used as a
mixture of two diastereomers (ca. 2:1) since these were not
separable in our hands. Under the standard reaction conditions
this ketone furnished a mixture of two diastereomeric tricyclic
products 11a and 11b in 35% combined yield. The configura-
tion of 11a was unequivocally determined by an X-ray crystal
structure analysis of the corresponding p-nitrobenzoate 12a ob-
tained by esterification of the tertiary alcohol under standard
conditions (Scheme 4, Figure 1) [13]. The configuration of the
second product 11b is only tentatively assigned as depicted
since the available data do not allow an unambiguous determi-
nation. Considering the result obtained with the cyclohep-
tanone derivative where two diastereomers could be assigned by
X-ray crystal structure analyses make the proposed trans-annu-
lation of the five- and six-membered rings fairly likely.
Figure 1: Molecular structure (ORTEP, [14]) of compound 12a (ther-
mal ellipsoids at 50% probability).
pound 13a was isolated. Fortunately, diastereomers 4a and 4b
The palladium-catalyzed cyclization discussed in this report could be separated by conventional column chromatography
was discovered with cyclohexanone derivative 4 and we there- and hence a detailed analysis of the stereochemical features of
fore tried to optimize the reaction conditions with this substrate. this transformation was possible. Configurationally homoge-
After extensive studies investigating different palladium cata- neous compound 4a furnished diastereomerically pure cycliza-
lysts, bases, additives, temperatures (with and without micro- tion product 13a in excellent yield, whereas epimer 4b was con-
wave) and reaction times we found the recorded conditions to verted into product 13b in 80% yield, again formed as a single
be most reliable. A mixture of the two diastereomers 4a/4b (ca. isomer (Scheme 5). An unequivocal configurational assignment
1:1) furnished the two isomeric cyclization products 13a and of 13a was possible by the X-ray crystal structure analysis of its
13b in varying yields and in several experiments only com- corresponding p-nitrobenzoate 14a (Figure 2) [15]. The config-
Scheme 4: Palladium-catalyzed cyclization of diastereomeric cyclopentanone derivatives 3a/3b to products 11a and 11b and synthesis of p-nitro-
benzoate 12a.
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Beilstein J. Org. Chem. 2016, 12, 1236–1242.
Scheme 5: Palladium-catalyzed cyclizations of diastereomeric cyclohexanone derivatives 4a and 4b leading stereoselectively to products 13a and
13b and structure of p-nitrobenzoate 14a.
Scheme 6: Palladium-catalyzed cyclizations of cycloheptanone deriva-
tives 5a and 5b leading to products 15a and 15b.
Figure 2: Molecular structure (ORTEP, [14]) of compound 14a (ther-
mal ellipsoids at 50% probability).
uration of compound 13b was tentatively assigned in analogy to
its lower and higher homologs.
With cycloheptanone derivatives 5a/b less efficient cycliza-
tions were observed. The mixture of diastereomers 5a/5b (ca.
1:1) provided a mixture of compounds containing the two
isomers 15a and 15b, from which pure 15a could be isolated
(Scheme 6). A diastereomerically enriched sample of 5b
afforded compound 15b in 45% yield as a single isomer. These
results were obtained employing microwave irradiation (400 W)
that allowed considerably shorter reaction times, however, the
yields were not strongly influenced by this modification. From
both product diastereomers crystals suitable for X-ray crystal
Figure 3: Molecular structure (ORTEP, [14]) of compound 15a (ther-
mal ellipsoids at 50% probability).
structure analyses could be obtained (Figure 3 and Figure 4)
[16,17]. Again, the configurations of the precursors are re-
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Beilstein J. Org. Chem. 2016, 12, 1236–1242.
magnesium. The related transformation described in this report
very likely involves an arylpalladium species as nucleophile
that is in situ generated from the aryl iodide moiety. Similar
palladium-catalyzed processes (palladium Barbier reactions) are
relatively rare (for a review, see [18]). Early studies were re-
ported by Y. Yamamoto et al. [19] and this group also
published examples involving an alkyne palladation step to
vinyl palladium intermediates that are able to undergo addi-
tions to carbonyl groups [20,21]. Very extensive investigations
with a variety of o-haloaniline derivatives as precursors have
been reported by the group of Solé, Bonjoch and Fernández
[22,23]. They also analyzed this reaction and the competing
enolate arylation by computational studies [24,25] (for a review,
see [26]). Singular contributions employing different systems
were contributed by other groups [27-29]. Scheme 8 shows a
typical example of Solé et al. [23], related to our systems,
furnishing a tricyclic compound in good yield with moderate
diastereoselectivity.
Figure 4: Molecular structure (ORTEP [14]) of compound 15b (ther-
mal ellipsoids at 50% probability).
flected in the product structure. Compound 5b provided prod-
uct 15b with trans-annulation of the two rings and we assume
that compound 15a with cis-annulated rings was formed selec-
tively from precursor 5a.
We also briefly studied the palladium-catalyzed cyclization of
p-methoxy-substituted aryl iodide 6a/b that led under the
standard conditions to a mixture containing compound 16
(Scheme 7). We cannot exclude that other regioisomers or even
primarily formed tetralin derivatives are in the crude product
mixture, but we isolated only compound 16 in pure form in 24%
Scheme 8: Typical palladium-catalyzed cyclization of an o-iodoaniline
derivative to a tricyclic tertiary alcohol as reported by Solé et al. [23].
yield. Not surprisingly, the p-methoxy substituent favored the The transformations described in the present report are highly
elimination of water from the primary addition product to stereoselective (we hesitate to use the term stereospecific here
generate the central double bond of 16.
since the mass balances are often too low to rigorously exclude
the formation of other diastereomers) since the configuration of
the cyclic precursor ketones 3–5 is transferred to that of the
Discussion
The nucleophilic addition of organometallics such as lithium, cyclization products as shown in Schemes 4–6. Surprisingly, the
magnesium or zinc organic compounds to carbonyl groups presence of excess of the base triethylamine and the fairly long
leading to alcohols is an important standard operation in organic reaction times do not lead to noticeable epimerization of the
synthesis providing high stereoselectivities in many cases. The precursor γ-ketoesters that would lead to an erosion of the ob-
in situ generation of the nucleophilic species from the corre- served stereoselectivity. In all examples the methoxycarbonyl
sponding organic halides in the presence of the carbonyl com- group and the hydroxy group are arranged trans to each other
pound is also known, e.g., the Barbier reaction employing irrespective of the configuration of the third stereogenic center
Scheme 7: Palladium-catalyzed cyclization of p-methoxy-substituted aryl iodide 6a/6b to compound 16.
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Beilstein J. Org. Chem. 2016, 12, 1236–1242.
at the bridgehead. A transition-state model that rationalizes this
observation is depicted in Scheme 9. We propose a four-center
interaction of the carbonyl moiety with the carbon–palladium
bond in the transition state (TS) and due to this highly ordered
arrangement only a boat-like transition state with a pseudo-
equatorial position of the methoxycarbonyl group seems to be
possible. The rigid benzene backbone further restricts the flexi-
bility of the system. This model explains the observed trans-
arrangement of the methoxycarbonyl group and the hydroxy
group leading to diastereomers a, if the hydrogen at C-1’ is in a
pseudo-equatorial position and diastereomers b if this atom
occupies a pseudo-axial position. This transition state is in
accordance with the model that has been proposed on the basis
of DFT calculations by Solé and Fernández [24-26].
Scheme 10: Possible mechanism of the reduction of palladium(II) to
palladium(0) by triethylamine (additional ligands at palladium are not
depicted for clarity of the presentation).
lent stereoselectivity and in moderate to very good efficacy. The
low mass balance observed in several cases may be due to
subsequent reactions such as simple de-iodination of the precur-
sor compounds or elimination of water in the products. How-
ever, in general none of these byproducts has been isolated. For
compound 2 the bulky isopropyl group slows down the addi-
tion to the carbonyl group and an enolate arylation was ob-
served instead as major reaction pathway. Although the scope
of the discovered aryl iodide addition to carbonyl groups may
be limited it is attractive since only low catalyst loadings are re-
quired and interesting products are formed with high stereose-
lectivity.
Supporting Information
Scheme 9: Proposed transition state (TS) explaining the stereoselec-
tive formation of cyclization products.
Supporting Information File 1
Characterization data and copies of 1H and 13C NMR
spectra.
The intermediate arylpalladium species is certainly generated by
the standard oxidative insertion of palladium(0) into the C–I
bond of the aryl iodide moiety. After the C–C bond formation
leading to the bi- or tricyclic products, palladium(II) has to be
reduced back to a palladium(0) species in order to allow a cata-
lytic use of the metal. It is well known that several reagents
(alkenes or alcohols [19]) are able to achieve this reduction. We
therefore assume that triethylamine is the reducing reagent
under the conditions employed in this study [30]. Possible
mechanisms for this process leading to the formation of an
iminium intermediate or a dehydrogenation of the amine are
depicted in Scheme 10.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-118-S1.pdf]
Acknowledgements
Generous support of this work by the Deutsche Forschungs-
gemeinschaft and by Bayer HealthCare AG is most gratefully
acknowledged.
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